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Preparation and Evaluation of ⁶⁸Ga-DOTA-hEGF for Visualization of EGFR Expression in Malignant Tumors

¹ Department of Organic Chemistry, Institute of Chemistry, Biomedical Centre, Uppsala University, Uppsala, Sweden
² Uppsala Imanet AB, Uppsala, Sweden
³ Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden

Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer. Methods: DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, ⁶⁸Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of ⁶⁸Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. Biodistribution and microPET visualization studies were performed in BALB/c nu/nu mice bearing A431 carcinoma xenografts. Results: A 1-min-long microwave-assisted labeling provided radioactivity incorporation of 77% ± 4%. Both cell lines demonstrated receptor-specific uptake of the conjugate, rapid internalization of the tracer, and good retention of radioactivity. Binding to both cell lines occurred with high affinity, approximately 2 nmol/L. The biodistribution study demonstrated accumulation of radioactivity in xenografts and in EGFR-expressing organs. The microPET imaging study enabled visualization of tumors and demonstrated quick—within 5 min—localization of radioactivity in tumors. Conclusion: ⁶⁸Ga-DOTA-hEGF has potential for imaging EGFR overexpression in tumors.

Key Words: ⁶⁸Ga • epidermal growth factor • PET • microPET • malignant tumors

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